Method of controlling lipids in the bloodstream

ABSTRACT

This invention relates to pharmaceutical compositions and methods for their administration and more specifically to lower alkanolamines. These compounds are administered to animals, including humans, for the purpose of controlling lipids, and especially triglycerides and cholesterol, in the bloodstream.

United States Patent [1 1 Roehm METHOD OF CONTROLLING LIPIDS IN THE BLOODSTREAM [76] Inventor: Dan Christian Roehm, 808 NE.

20th Ave., Fort Lauderdale, Fla. 33304 [22] Filed: Feb. 9, 1972 [21] Appl. No.: 224,964

[52] U.S. Cl. 424/325 [51] Int. Cl. H61k 27/00 [58] Field of Search 424/325 [56] References Cited OTHER PUBLICATIONS Chemical Abstracts 53:143l9a, (1959).

[451 July 1, 1975 Primary ExaminerJerome D. Goldberg Attorney, Agent, or FirmCushman, Darby & Cushman [5 7 ABSTRACT 12 Claims, No Drawings METHOD OF CONTROLLING LIPIDS IN THE BLOODSTREAM BACKGROUND OF THE INVENTION Lower alkanolamines have long been known as carriers. diluents and salt-formation compounds for use with pharmacologically active compounds. For example, triethanolamine has been used as a diluent, and the diethanolamine salt of sulfisoxazole is used for both intravenous and ocular administration. Theophylline (1,3- dimethylxanthene) monoethanolamine is a preferred salt form of theophylline for intramuscular and intrave nous injection.

Investigators have reported effects of alkanolamines and amine-alcohols (Clinical Research, June, 1959, pp. 142-444) and Dayton in Circulation Research, VI, pp. 27 [-274, reported that diethanolamine exaggerated induced hypercholesterolemia.

BRIEF DESCRIPTION OF THE INVENTION It has now been discovered that lower alkyl amines are effective for controlling the liquid content in the bloodstream when administered while the recipient is in a fasting state. The preferred amines are mon-, diand triethanolamine.

DETAILED DESCRIPTION OF THE INVENTION It has now been discovered that certain amines are quite active in regulating the lipid metabolism of the liver when administered under certain fasting conditions, as hereafter fully defined. Although not bound by any particular theory, the amines appear to stimulate the lipid catabolism (combustion) function of the liver, and thus lower the serum lipid content of the bloodstream. It appears that the alkyl amines cause the liver to function for a period of time, as if in a state of extreme fasting or starvation, i.e. the liver burns fats al most exclusively. Thus, the amines are useful for treating a variety of illnesses where the lowering or controlling of the content of blood lipids is desired, e.g., angina, atherosclerosis and diabetes.

The compounds useful in the present invention comprise the lower alkyl amines. The alkyl groups may be either straight-chained, such as methyl, ethyl, propyl, or butyl, or branched, such as isopropyl and isobutyl. The amines may be substituted and are primary, secondary or tertiary amines of the formula:

where R R and R are hydrogen and alkyl groups of from the nitrogen atom. The preferred embodiments are monoethanolamine, diethanolamine and triethanolamine, especially diethanolamine.

The amines of the present invention are basic in nature, and it is preferred to adjust the pH thereof to between 4 and 8, more preferably to essentially neutralize the amines, with a nontoxic salt-forming acid. The salts of the amines may be formed with acids such as a mineral acid, e.g. hydrochloric acid, nitric acid and sulfuric acid, or an organic acid such as acetic acid, citric acid, tartaric acid, lactic acid, ascorbic acid, methanesulfonic acid, ethanesulfonic acid, quinic acid, 3- hydroxy-Z-naphthoic acid, naponic acid (LS-naphthalene-disulfonic acid), acetylsalicyclic acid, salicyclic acid, mucic acid, muconic acid and the like. Hereinafter the term amines is intended to include the aforementioned salts thereof.

According to the present invention, the amines are prepared for administration to the patient either as a solution, suspension or elixir, or as a tablet, torche, capsule or the like. Thus, the amines may be mixed with any desired inert diluent, extender, carrier, tableting powder, etc., but the amines will be the only active ingredient. Thus, in this specification, the compositions to be administered are only of inert ingredients and the present active amines and this definition is referenced as consisting essentially of the defined amines.

The compositions may be intravenously or subcutaneously administered, but oral administration is more convenient and enjoys a wider patient acceptability. Thus, oral administration is preferred although other methods of administration may be used if desired.

The conditions of the administration of the amines are of utmost importance in achieving the desired result. Unexpectedly, it has been found that the effects of the amines depend on the lipid content of the bloodstream when the amines are administered to the patient. The effects of administration of the amines may be diametrically opposite to the desired effect, when the lipid content of the bloodstream is elevated from relative concurrent ingestion of food. Thus, higher post 'prandial lipid contents in the bloodstream must be up to 6 carbon atoms, provided that not each of R R and R is hydrogen. The alkyl groups may be substituted with at least one and up to three OH groups or substituted with one aryl group, e.g. benzene and toluene groups. However, it has been found that the hydroxy substituted alkyl amines, i.e. where at least one of R R and R are alkanol groups, are far more effective than the unsubstituted alkyl or substituted aryl alkyl amines. Thus, the alkanol amines are a superior form of the invention. With polyhydroxy alkanol amines. it is preferred that the OH groups be on different carbon atoms and preferably on carbon atoms away avoided or the effect of administration of the amine will be opposite to the desired effect and may even be dangerous. Accordingly, the amines are administered only when the lipid content of the blood is below a maximum level. However, since the response to the amines will vary somewhat from patient to patient, even with essentially the same absolute level of lipids in the bloodstream, the maximum level of lipids in the bloodstream for any one patient should be determined by appropriate tests. Thus, the blood should be tested 1 to 2 hours after administration of the amines, and if the lipid, e.g. triglycerides, content abnormally increases, then the blood of that patient contained too high a lipid level for administration of the amine. If the lipid content decreases below the pretreatment level, then the patient had less than the maximum permissible amount of lipids in the bloodstream and the administration of the amine will produce the desired results. Thus, a maximum lipid content for any particular patient can be established. This lower level of lipids in the bloodstream of the patient to whom the present amines are administered and which administration results in the lipid content of the blood dropping to below its pre-treatment content is defined herein as the fasting state of the patient. This fasting state can be obtained by simply administering the amines only at a time significantly after the last substantial food intake and significantly before the next substantial food intake of the patient.

The significance of the conditions under which the amines are administered can be understood from Table A where the miligram of triglycerides (TG) in the bloodstream are shown for various periods after a one gram dose of diethanolamine hydrochloride, calculated as the amine, is given at the indicated hours before or after the consumption of a high fat meal, i.e. for test purposes the ingestion of 43 pound of butter. Normal levels of serum triglycerides (TG) without diethanolamine (DEA) are indicated by the CONTROL data. lt is noted that a gradual rise in serum triglycerides is the normal and physiological occurrence. Table A clearly shows that a substantial and potentially dangerous increase in the serum triglyceride level occurs when administration is close to the ingestion of a fatty meal. In fact, instead of lowering the triglyceride response below the CONTROL level obtained with ingestion of a fatty meal, the triglyceride level increases much more than in the CONTROL test.

TABLE A 1 l86l5 reports the toxicity of diethanolamine in mice as 2050 mg/kg, rabbit 1000 mg/kg and guinea pig 620 mg/kg. These values are given to illustrate the substantially innocuous character of the present amines.

As noted hereinbefore, oral administration of the amines may be by way of tablets, capsules, elixirs, syrups and suspensions or as desired. Preferably oral administration is by way of tablets or capsules which are formulated in manners well known to pharmaceutical art, utilizing any inert U.S. pharmacopoeia excipients such as lactose, starch, terra alba, magnesium stearate, calcium sulfate, glycerylmono or distearate, gelatin, or wax. Or if the administration is subcutaneously, any U.S.P. injection vehicle such as sterile water or saline solution may be used. However, it is not necessary that the amines be diluted or extended at all and may be given in the undiluted or unextended form. If course, as noted above, it is preferred that the amine be neutralized with a pharmaceutically acceptable acid.

As noted hereinbefore, diethanolamine was considered by the art as a counter-productive in connection DEA Given Number of Hours Before and After meal number of hours after giving DEA Mg. 7c of Triglycerides in blood when tested +5 +6 hrs. 641

DEA is Diethanolumine Meal consisted of2 oz. of butter.

Thus, it has been discovered that the present amines have the opposite effect to that expected (i.e. raising the lipid level in the blood), but this unexpected effect is observed only when the amines are taken in the fasting state, as hereinbefore defined. As illustrated by Table A, to ensure the defined fasting state, the amines should be given no later than two hours before a fatty meal and no earlier than one hour after a fatty meal. In this regard, a fatty meal is defined as a meal containing at least 400 calories and containing at least 2 ounces of fat.

For purposes of the present specification, the term lipid is used in the broader sense and is intended to embrace related compounds, especially cholesterol. Thus, in referencing lipid levels in the blood and in referencing the control of lipids, related compounds including cholesterol are intended to be embraced thereby.

The dosage may be from about mg. to about 20 grams (calculated as the amine) on a daily basis, but generally, a reasonably consistent serum triglyceride level may be maintained with daily dosages in the range of from 50 mg. to 10 grams, especially from 50 mg. to 2 or 4 grams. Of course, the dosage may be distributed throughout the day, e.g. 2 to 6 times a day to provide a total daily dosage in the ranges noted above. Of

course, it will be appreciated that higher and lower amounts may be used depending upon the patients requirements. These dosage levels do not approach the toxic limits. For example, Chemical Abstracts 73:

with hypercholesterolemia. And indeed, if an alkanolamine is taken close to or with a meal, as was the case in the Dayton paper referenced above, and as shown in TABLE A, an abnormal elevation of triglycerides and total lipids in the serum (sometimes potentially dangerous) and prolongation of postprandial chylomicronemia occur. Thus, it is critical that the amine be administered to the patient under fasting conditions. The following examples will serve to further show the importance of these conditions in terms of results obtained. It should also be noted that the examples show, in addition to lower lipid levels, that the desaturation of serum fatty acids also occurs. In the following examples, unless otherwise indicated, all parts and percentages are by weight, all dosages are calculated as the amine base and all subjects are human.

EXAMPLE 1 In this experiment, diethanolamine I-ICl was administered to determine the extent of depression of the socalled lipid profile in the blood serum. The lipid levels of the subject were measured, and the subject received diethanolamine HCl in the form of a liquid taken orally in a single daily dosage of 250 mg (calclulated as the amine) at bedtime, which was four hours after the last meal and eight hours before breakfast. This was continued for a period of days. As seen below, significant decreases in mg. of total lipids (T.L.) triglycerides (T.G.), phospholipids (P.L.) and cholesterol (Chol.) took place. Control indicates the respective lipid levels prior to commencin diethaolamine HCI administration.

It was observed that the diethanolamine HCI was tolerated without any side effects or laboratory abnormalities during the 70day course of therapy.

EXAMPLE 2 In the manner of Example 1, 250 mg. of diethanolamine hydrochloride, calculated as the amines, was orally administered to a subject at bedtime. After 24 days of treatment, test results are shown in TABLE C using the lipid profile designated as above.

TABLE C Lipid Control After 24 Days T.l 931 637 T0. 347 135 PL. 260 I37 Chol. 300 266 The treatment was continued for an additional days (a total of 44 days) and the serum cholesterol had fallen to 223 mg. 72 where it remained for an additional three months of treatment in the same manner. Thereafter, the dosage of diethanolamine HCI, calculated as the amine) was increased to 500 mg. twice daily, but never closer than 2 hours to a meal, and continued for 30 days. On this latter regimen a further decline in serum cholesterol to 175 mg. 7: occurred. This amounts to a 40% decrease in cholesterol over the control and compares very favorably with other known methods of cholesterol control, where average decreases of 20-2571 are usually reported. The marked decrease in triglyceride levels from 347 to 135 mg. or 61% indicates the high degree of activity of the present amines. The liver function studies were normal during the entire treatment period.

EXAMPLE 3 The subject of this example had a pretreatment serum cholesterol value of 295 mg. Oral daily dosages of 250 mg. of diethanolamine HCI, calculated as the amine, were given at bedtime on an empty stomach. Serum cholesterol measurements at approximately 2 week intervals were 295,255,246, 242, 230, 222, 205, 198, 207 mg.%. By giving two dosages of 250 mg. each per day, the cholesterol level decreased to about 160 mg. 7:.

No side effects were reported by this subject. An isolated dose of 5 grams diethanolamine HCI, calculated as the amine, was administered to the subject and the only reported side effect was mild diarrhea. Liver function studies, urinalyses, differential blood counts and other blood chemistry studies showed no abnormalities.

EXAMPLE 4 The subject had a control serum triglyceride level of 252 mg.% after 14 hours without food. 0.5 grams of diethanolamine HCI, calculated as the amine, was given orally with a balanced meal (approximately 1000 calories and approximately 2.0 oz. of fat). 15 hours later the serum triglyceride level was 522 mg. 70. The serum was noticeably turbid throughout with some milkiness. This indicated prolonged postprandial chylomicronemia. Thus, administering the amine with a meal caused increased hyperlipidema, as was reported in the prior art. Also, it is clear that administration of the amine with a meal additionally produces a prolongation of the elevation of serum triglycerides.

EXAMPLE 5 Triethanolamine HCI was orally administered to a subject in the single dosage of 1.0 gram, calculated as the amine, 4 hours after a meal and 4 hours prior to further ingestion of food. This regimen was continued daily and in two weeks serum cholesterol declined from 275 mg. to 225 mg.% and serum triglycerides from 145 to mg.%. In this case, triethanolamine effectively lowered the serum cholesterol.

EXAMPLE 6 A subject ate no food during a 14 day period of fasting. At the end of the second day, strong ketonuria developed. For the remainder of the fast, from 15 to 30 grams per day of diethanolamine HCI, calculated as the amine, were administered orally and urine tests for ketones (Ketostix) showed negative or trace results, Serum uric acid did not rise, which is evidence that ketonemia was not present. Finally, the subject experienced none of the narcotizing effects of ketosis that would be otherwise expected and could perform daily routines normally. During this time of heavy endogenous fat catabolism, diethanolamine altered the catabolism beneficially to the extent that toxic ketone metabolites were not found in the urine. Slight diarrhea was noted at the higher daily dosage levels.

EXAMPLE 7 A subject exhibited a normal Iodine Number by Chain Length of between 1 l2 and 107. After one month of orally administering diethanolamine HCI in a daily dosage of 0.25 grams (calculated as the amine) at bedtime, this figure rose to 144.2. At the conclusion of the treatment and after 18 days of no medication, this value fell to 121.5. A second subject exhibited a normal Iodine Number by Chain Length of between 118 and l 17. After three months treatment of orally administering 0.25 grams of diethanolamine HCI (calculated as the amine) daily at bedtime, the Iodine Number rose to between 137 and 154. Thus, it is clear that the diethanolamine also stimulated the liver to produce greater unsaturation of fats. This effect is, therefore, also beneficial in treating arteriosclerosis.

EXAMPLE 8 A hydrochloride of a polyamine polyol known as monohydroxyethyl, trihydroxyisopropyl-ethylenediamine of the following formula:

CHzcH oH GMW 278.39

was administered intravenously to a 35 pound dog in a 5 dosage of 2.89 g, calculated as the amine. The dog was arteriosclerosic and had hyperlipema with elevation of the serum total lipids to about 1570 mg. Six hours after injection of the amine, the total lipids had fallen TABLE E Relation of DEA* 1 A B I DEA* to Fatty Previous Initial Final (6 hrs) Ratio Meal 24 Hours Triglycerides Triglycerides A/B,- B/A CONTROL (no DEA*) no 35.7 641 L8 2 hours no 320 l 398 1.2 1 hour no 536 l43l 2.6 .l hour yes 212. 658 3.] hour no 504 I325 2.6 1 hour yes 276 478 L7 1 hour no 258 698 2.7 2 hours yes I73 453 2.6 3 hours yes 320 433 1.4 5 hours 1.8

yes 300 534 .Diethanolamine hydrochloride to 680 In the same period of time, total serum cholesterol declined from 260 to 192 mg. Prior to injection, blood glucose was measured at 115 mg. but fell to 66 mg. in about 4 hours.

EXAMPLE 9 aryl-alkanolamine, 2,2',metatolyliminodiethanol was given intravenously inan amount of 6 grams to a pound canine. Blood glucose was initially 117 mg.

% but rose in 30 minutes to 142 and, after 4 hours, measured 104 mg. Serum cholesterol prior to drug administration was 218 mg. and after 4 hours measured to 190 mg.

EXAMPLE 10 The normal triglyceride mg.% content of blood serum and the normal increase of triglyceride mg.% content of blood serum in 6 hours after the consumption of a 'meal of 500 calories and 2 02s. of fat was establishe'd' (CONTROL in Table E). In one series of tests, 1 gram of diethanolamine HCl (DEA), calculated as the amine, was administered when a dose of diethanolamine had not been received within 24 hours. The

administration was at the indicated hours before a A is shown. As can be seen, when the subject has not received diethanolamine within 24 hours, the proximity of fatty meal and diethanolamine ingestion results in the largest absolute increase of triglycerides. Moreover, the ratio of Final (6 hours) Triglycerides to Initial Triglycerides is about 2.5 to 3.1 when the diethanolamine administration and fatty food ingestion are within 1 hour of each other. It is well known that as the serum becomes more hyperlipidemic, the blood be- As can be appreciated from the above, the invention is applicable for controlling and reducing the lipid (including cholesterol) content of blood of animals, including humans, The dosage ranges given above are in connection with humans and with the assumption of pounds body weight. However, for other body weights of humans or for other animals, the dosages may be correspondingly adjusted.

It should also be appreciated that the amines and the salts thereof, may bein the form of the corresponding diamine and triamine, i.e. polyamines Thus, it is intended that these polyamines be embraced by the definition of the amines useful in the invention, as hereinbefore defined. I I

It should also be appreciated'that various modifications within the scope and spirit of the spresent disclosure will be immediately apparent to those skilled in the art and those modifications are intended to be embraced by the following claims.

What is claimed is:

l. A method of lowering the serum lipids of animals comprising administering an effective lipid lowering amount of a composition to an animal host in need of said lipid lowering and in such a fasting state that the animal has not had a substantial food intake within 2 hours before or 1 hour after the administration of the composition, whereby the lipid content of the blood drops below the'preadministration content, said substantial food intake being at least the equivalent of 400 calories and 2 ounces of fat and said composition consisting essentially of diethanolamine or the pharmaceutically acceptable nontoxic salts thereof.

2. The method of claim 1 wherein the composition is at a pH of between 4 and 8.

3. The method of claim 1 wherein the pH of the composition is essentially neutral.

4. The method of claim I wherein the salt is hydro- 6. The method of claim wherein from about 50 mg fering from atherosclerosis. to about 4 g per day of the said composition are admin- 10. The method of claim 1 wherein the animal is a istered. human.

7. The method of claim 1 where the lipid is a triglyc- 11. The method of claim 1 wherein the animal is eride. 5 human suffering from diabetes.

8. The method of claim 1 where the lipid is choles- 12. The method of claim 1 wherein the animal is sufterol. fering from angina.

9. The method of claim 1 wherein the animal is suf- UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,892,865

DATED r July 1, 1975 INVENTOR(S) I DAN CHRISTIAN ROEHM it is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 23, "liquid" should be -lipid-.

Column 8, line 13, under "TABLE E", last column on right, "Ratio A/B-B/A" should be -Ratio B/A--.

Signed and Scaled this twenty-fifth D ay 0f November 19 75 [SEAL] A ttest:

RUTH c. MASON c. MARSHALL DANN Arresting Officer Commissioner ofParents and Trademarks 

1. A METHOD OF LOWERING THE SERUM LIPIDS OF ANIMALS COMPRISING ADMINISTERING AN EFFECTIVE LIPID LOWERING AMOUNT OF A COMPOSITION TO AN ANIMAL HOST IN NEED OF SAID LIPID LOWERING AND IN SUCH A FASTING STATE THAT THE ANIMAL HAS NOT HAD A SUBSTANTIAL FOOD INTAKE WITHIN 2 HOURS BEFORE OR 1 HOUR AFTER THE ADMINISTRATION OF THE COMPOSITION, WHEREBY THE LIPID CONTENT OF THE BLOOD DROPS BELOW THE PREADMINISTRATION CONTENT, SAID SUBSTANTIAL FOOD INTAKE BEING AT LEAST THE EQUIVALENT OF 400 CALORIES AND 2 OUNCES OF FAT AND SAID COMPOSITION CONSISTING ESSENTIALLY OF DIETHANOLAMINE OR THE PHARMACEUTICALLY ACCEPTABLE NONTOXIC SALTS THEREOF.
 2. The method of claim 1 wherein the composition is at a pH of between 4 and
 8. 3. The method of claim 1 wherein the pH of the composition is essentially neutral.
 4. The method of claim 1 wherein the salt is hydrochloride.
 5. The method of claim 1 wherein from about 50 mg to about 20 g per day of the said composition are administered.
 6. The method of claim 5 wherein from about 50 mg to about 4 g per day of the said composition are administered.
 7. The method of claim 1 where the lipid is a triglyceride.
 8. The method of claim 1 where the lipid is cholesterol.
 9. The method of claim 1 wherein the animal is suffering from atherosclerosis.
 10. The method of claim 1 wherein the animal is a human.
 11. The method of claim 1 wherein the animal is human suffering from diabetes.
 12. The method of claim 1 wherein the animal is suffering from angina. 